1. Samson, Kurt

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Donald Metcalf, MD, considered "the father of modern hematology," died Dec. 15, at age 85, surrounded by his family, in Melbourne, Australia.

DONALD W. METCALF, M... - Click to enlarge in new windowDONALD W. METCALF, MD. DONALD W. METCALF, MD (1929-2014)

Professor Emeritus at the University of Melbourne and the Cancer Council Victoria's Carden Fellow in the Division of Cancer and Hematology at the Walter and Eliza Hall Institute of Medical Research, he was the first to discover colony-stimulating factors (CSFs), hormones that control white blood cell production to bolster recovery after cancer treatment.


Metcalf worked at the Walter and Eliza Hall Institute for 60 years, from 1954 to 2014. After he developed pancreatic cancer this past August, he continued his research at home until October, when he conducted his final experiment, his colleague, Douglas Hilton, PhD, the Institute's Director and a molecular biologist, said in an interview.


Metcalf's pioneering research focused on the control of blood cell formation and, specifically, leukemic cells. In 1965 he co-developed a series of specialized culture techniques that allowed scientists to grow various types of blood cells, after which he discovered colony-stimulating factors, which control the formation of white blood cells that resist infection.


He and his colleagues next discovered the effectiveness of two primary white blood cell regulators-granulocyte-macrophage colony-stimulating factors and granulocyte colony-stimulating factors-to speed regrowth of blood cells after chemotherapy and bone marrow and peripheral blood transplants.


His early studies on white blood cell regulators led him to hypothesize that there was some hormonal process involved in controlling their production-substances he called colony stimulating factors. For more than 50 years he pursued his understanding of CSFs, and helped lead researchers to identify and purify four separate stimulating factors. He and his team were also among the first researchers in the world to discover the genes for CSFs.


A leading researcher in international clinical trials of CSFs in the 1980s, Metcalf came to better understand how and why these factors boost immune cell numbers in cancer patients whose immune systems were weakened by chemotherapy. This led to development and eventual approval of the drug G-CSF (filgrastim, Neupogen).


Revolutionized Stem Cell Transplantation

As well as boosting the immune system in chemotherapy patients and in other immune deficiencies, CSFs revolutionized blood stem cell transplantation. It was later found that CSFs also contribute to such diseases as rheumatoid arthritis, and medications that block CSF function are currently entering clinical trials.


Metcalf later investigated stem cells, CSF receptors, cell survival, and suppressors of cell signaling. He was involved in discovering a multiple-action growth factor, the leukemia inhibitory factor.


Jose Carreras

Among the first patients in the world to receive treatment with a colony-stimulating factor was opera tenor Jose Carreras when he developed acute lymphoblastic leukemia that failed to respond to initial treatment. He received CSF therapy in 1987, recovered, and today continues to raise money to help leukemia patients and advance research through the establishment of the Jose Carreras International Leukemia Foundation.


During the course of Metcalf's career, he mentored hundreds of research students and authored 700+ papers on his findings; he also holds 21 patents.


Among the many honors and awards he received were the Albert Lasker Award for Clinical Medical Research, the Gairdner Foundation International Award, the Royal Medal of the Royal Society, the Victoria Prize, and the Lifetime Achievement Award from American Association for Cancer Research in 2007.


"As an experimental pathologist, I have studied the manner in which mature blood cells are formed by ancestral cells in the bone marrow. This required the development of clonal culture systems, allowing the progeny of individual cells to be analyzed," Metcalf wrote for a biographical sketch for the National Academy of Sciences at the time of his election as a member in 1987.


"The four CSFs were purified and can now be mass produced in recombinant form. The CSFs are now widely used clinically to stimulate blood cell formation, particularly in patients undergoing chemotherapy where the treatment damages bone marrow cells. We are currently generating mice with homozygous inactivation of genes encoding blood cell regulatory factors or their receptors to establish the precise functions attributable to each factor. Parallel studies are using mutagenized receptors to establish the domains in each receptor chain initiating each of the variety of signaling cascades required to mediate the pleiotropic actions each regulator has on responding cells."


Millions of Patients Helped

"Over the past 20 years, more than 20 million cancer patients have been treated with CSFs and, as a result, have been given the best possible chance of beating their cancer," Hilton said. "There can be no greater legacy for a medical researcher."


In a tribute, he along with Professors Warren Alexander, PhD, and Nicos Nicola, PhD, Heads of the Division of Cancer and Hematology at the Institute, wrote the following:


"'Don,' to most everyone with whom he worked, was a Colossus of science who, working at the Walter and Eliza Hall Institute and supported by the Cancer Council of Victoria from 1954 to 2014, stood astride the world of hematology for 60 years.


"In 1964, studying leukemia, he and Ray Bradley, from The University of Melbourne, discovered it was possible to grow bone marrow cells in plates of partly set agar jelly. Don's genius lay not in this breakthrough, but in the realization that it could be used to understand the cellular basis of blood cell production and to discover the hormones, which he named colony-stimulating factors."


Metcalf characterized blood stem cells and their daughter cells, which produce multiple types of white blood cells that fight infection and prevent bleeding.


"In doing so he made the blood cell system the 'poster child' of medical research and shone a light into the darkness for those who followed him to work on understanding other tissues such as the breast, skin, and colon," Hilton, Alexander, and Nicola wrote.

Figure. A stamp was ... - Click to enlarge in new windowFigure. A stamp was created in his honor in 2002 as part of the Australian Legends series, which commemorate Australians "who have made lifetime contributions to the development of the Commonwealth's national identity and character."

"Despite Don's profound fundamental discoveries, which shaped our basic understanding of how blood cells are made and work, he also mentored hundreds of students-guiding many into careers as oncology researchers.


"Don also understood his limitations. Although he was comfortable with cells, he was wary of molecules such as DNA and protein. Nevertheless, Don knew he needed collaborators who would take him out his comfort zone and help him fulfill his ambition of delivering health benefits from his discoveries and so he assembled a team of researchers who worked with him for 40 years.


"Don's ability to identify a glimmer of talent in younger researchers and mold them into a cohesive, loyal, and vibrant team, that consistently came up with ground-breaking discoveries, was remarkable. Decades ahead of its time, his model of collaborative, multidisciplinary science shaped the culture of the Walter and Eliza Hall Institute and is now seen as almost mandatory if big problems are to be tackled and significant breakthroughs are to be made in medical science."


He is survived by his wife, Josephine, four daughters, and six grandchildren.


In recognition of his work with young scientists, the Walter and Eliza Hall Institute of Medical Research established the Metcalf Scholarship Fund ( to support promising young researchers.